6ek3: Difference between revisions
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==PARP15 CATALYTIC DOMAIN MUTANT (Y598L) IN COMPLEX WITH OUL35== | |||
<StructureSection load='6ek3' size='340' side='right' caption='[[6ek3]], [[Resolution|resolution]] 1.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6ek3]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EK3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EK3 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=OUL:4-(4-aminocarbonylphenoxy)benzamide'>OUL</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/NAD(+)_ADP-ribosyltransferase NAD(+) ADP-ribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.30 2.4.2.30] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ek3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ek3 OCA], [http://pdbe.org/6ek3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ek3 RCSB], [http://www.ebi.ac.uk/pdbsum/6ek3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ek3 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/PAR15_HUMAN PAR15_HUMAN]] Transcriptional repressor. Has ADP-ribosyltransferase activity. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Human Diphtheria toxin-like ADP-ribosyltranferases (ARTD) 10 is an enzyme carrying out mono-ADP-ribosylation of a range of cellular proteins and affecting their activities. It shuttles between cytoplasm and nucleus and influences signaling events in both compartments, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signaling and S phase DNA repair. Furthermore, overexpression of ARTD10 induces cell death. We recently reported on the discovery of a hit compound, OUL35 (compound 1), with 330nM potency and remarkable selectivity towards ARTD10 over other enzymes in the human protein family. Here we aimed at establishing a structure-activity relationship of the OUL35 scaffold, by evaluating an array of 4-phenoxybenzamide derivatives. By exploring modifications on the linker between the aromatic rings, we identified also a 4-(benzyloxy)benzamide derivative, compound 32, which is potent (IC50=230nM) and selective, and like OUL35 was able to rescue HeLa cells from ARTD10-induced cell death. Evaluation of an enlarged series of derivatives produced detailed knowledge on the structural requirements for ARTD10 inhibition and allowed the discovery of further tool compounds with submicromolar cellular potency that will help in understanding the roles of ARTD10 in biological systems. | |||
4-(Phenoxy) and 4-(benzyloxy)benzamides as potent and selective inhibitors of mono-ADP-ribosyltransferase PARP10/ARTD10.,Murthy S, Desantis J, Verheugd P, Maksimainen MM, Venkannagari H, Massari S, Ashok Y, Obaji E, Nkizinkinko Y, Luscher B, Tabarrini O, Lehtio L Eur J Med Chem. 2018 Jun 20;156:93-102. doi: 10.1016/j.ejmech.2018.06.047. PMID:30006177<ref>PMID:30006177</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6ek3" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Lehtio, L]] | [[Category: Lehtio, L]] | ||
[[Category: Maksimainen, M M]] | |||
[[Category: Inhibitor]] | |||
[[Category: Oul35]] | |||
[[Category: Signaling protein]] | |||
[[Category: Transferase]] | |||
Revision as of 10:21, 25 July 2018
PARP15 CATALYTIC DOMAIN MUTANT (Y598L) IN COMPLEX WITH OUL35PARP15 CATALYTIC DOMAIN MUTANT (Y598L) IN COMPLEX WITH OUL35
Structural highlights
Function[PAR15_HUMAN] Transcriptional repressor. Has ADP-ribosyltransferase activity. Publication Abstract from PubMedHuman Diphtheria toxin-like ADP-ribosyltranferases (ARTD) 10 is an enzyme carrying out mono-ADP-ribosylation of a range of cellular proteins and affecting their activities. It shuttles between cytoplasm and nucleus and influences signaling events in both compartments, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signaling and S phase DNA repair. Furthermore, overexpression of ARTD10 induces cell death. We recently reported on the discovery of a hit compound, OUL35 (compound 1), with 330nM potency and remarkable selectivity towards ARTD10 over other enzymes in the human protein family. Here we aimed at establishing a structure-activity relationship of the OUL35 scaffold, by evaluating an array of 4-phenoxybenzamide derivatives. By exploring modifications on the linker between the aromatic rings, we identified also a 4-(benzyloxy)benzamide derivative, compound 32, which is potent (IC50=230nM) and selective, and like OUL35 was able to rescue HeLa cells from ARTD10-induced cell death. Evaluation of an enlarged series of derivatives produced detailed knowledge on the structural requirements for ARTD10 inhibition and allowed the discovery of further tool compounds with submicromolar cellular potency that will help in understanding the roles of ARTD10 in biological systems. 4-(Phenoxy) and 4-(benzyloxy)benzamides as potent and selective inhibitors of mono-ADP-ribosyltransferase PARP10/ARTD10.,Murthy S, Desantis J, Verheugd P, Maksimainen MM, Venkannagari H, Massari S, Ashok Y, Obaji E, Nkizinkinko Y, Luscher B, Tabarrini O, Lehtio L Eur J Med Chem. 2018 Jun 20;156:93-102. doi: 10.1016/j.ejmech.2018.06.047. PMID:30006177[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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